Dear Editor,

N-glycanase 1 (NGLY1) deficiency is an ultra-rare, autosomal recessive disorder caused by loss of function variants in NGLY1 [1]. It is categorized as the first known congenital disorder of deglycosylation [2]. The disorder is characterized by five core features: (1) global developmental delay and/or intellectual disability, (2) a primarily hyperkinetic movement disorder (3) transient elevation of liver transaminases (4) hypo- or alacrima, and (5) peripheral neuropathy [1, 3, 4].

Additionally, acquired microcephaly, hypotonia, EEG abnormalities with or without overt seizures, brain imaging abnormalities, GI disturbances, and a history of intrauterine growth restriction (IUGR) were also reported in some cases. Some patients were noted to have dysmorphic features, but overall these were not considered to be particularly prominent [1]. The differential diagnosis of inherited conditions featuring alacrima and neurological dysfunction is limited, and we did not identify any other disorder associated with both alacrima and choreoathetosis [1].

In NGLY1 deficiency, the mutations in the NGLY1 gene result in reduced or absent N-glycanase 1 activity. This leads to the accumulation of abnormal glycoproteins within the ER, disrupting the normal protein quality control mechanisms. As a result, the misfolded proteins cannot be properly degraded and cleared from the cells.

At present, the condition is diagnosed via genetic testing. However, screening for the recently described NGLY1 Deficiency biomarker, GlcNAc-Asn, may help identify patients and increase the rate of diagnosis [5]. To determine the severity of the illness and the requirements of a person with NGLY1 deficiency the evaluations necessary for initial diagnosis include radiological and orthopedic assessment including DXA scan, neurologic and neurodevelopmental evaluation of cognitive abilities, ophthalmologic evaluations for hypolacrima and lacrimal disease, GI evaluations of transaminase levels, and constipation.

Treatment options are presently limited to supportive care. However, a gene therapy is currently under development. Thus, it is increasingly important to identify affected families to participate in patient registries, natural history studies, and interventional studies [6].

We strongly believe that genetic counseling should be offered to young adults who are carriers or at risk of being carriers. It is crucial to determine genetic risk, confirm carrier status, and explore prenatal or preimplantation genetic testing options before planning for pregnancy. Preservation of DNA should be considered which allows for re-evaluation and the possibility of identifying genetic causes that were previously unknown, thereby offering renewed hope for accurate diagnoses and targeted treatments.